4-Fluoroaniline → 1,2-Bis(4-fluorophenyl)-1H-indole-5-carboxylic acid

HRID 1472501Notes

Reaction equation

HRID 1472501 reaction equation
Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[F:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC([O-])(C)C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[F:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]2[C:2]3[C:3](=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:10][CH:11]=3)[CH:12]=[C:13]2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:24][CH:23]=1

Participants

7

Reactant 4

HCID 97314-FluoroanilineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23665647Potassium tert-butoxideHCID 70654480Methyl 4-chloro-3-(2-(4-fluorophenyl)ethynyl)benzoate

Product 1

HCID 601679391,2-Bis(4-fluorophenyl)-1H-indole-5-carboxylic acid

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

Under an inert atmosphere of nitrogen, a mixture of methyl 4-chloro-3-(2-(4-fluorophenyl)ethynyl)benzoate (200 mg, 0.69 mmol, 1.00 equiv), 4-fluoroaniline (152.8 mg, 1.39 mmol, 2.00 equiv), X-Phos (65.2 mg, 0.14 mmol, 0.20 equiv), Pd2(dba)3 (63.8 mg, 0.07 mmol, 0.10 equiv), t-BuOK (388.8 mg, 3.47 mmol, 5.00 equiv), and toluene (8 mL) was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated in vacuo, and purified via silica gel column chromatography (ethyl acetate/petroleum ether (1:1)). The crude product (160 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (MS-Directed)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (50% CH3CN up to 70% in 10 min); Detector, UV 254 nm. This resulted in 26 mg (11%) of 1,2-bis(4-fluorophenyl)-1H-indole-5-carboxylic acid as a white solid.

Workup

  1. concentrationThe resulting mixture was concentrated in vacuo
  2. custompurified via silica gel column chromatography (ethyl acetate/petroleum ether (1:1))
  3. customThe crude product (160 mg) was purified by Prep-HPLC with the following conditions (AGILENT Pre-HPLC (MS-Directed))
  4. waitmobile phase, water with 0.05% TFA and CH3CN (50% CH3CN up to 70% in 10 min)
  5. customThis resulted in 26 mg (11%) of 1,2-bis(4-fluorophenyl)-1H-indole-5-carboxylic acid as a white solid

Sources & evidence

ORD record
ord-0f3805d164ae4ca39a63e5c76404f5b4
Source dataset
uspto-grants-2015_04
Patent number
US09012637B2

Reaction notes

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